The present invention is directed to phenylazole compounds, processes for producing the phenylazole compounds and drugs for hyperlipemia containing the said phenylazole compounds as the active ingredients.
Serious heart diseases, such as myocardial infarction, are a disease induced by hyperlipemia which is the primary factor causing of arteriosclerosis. Presently, three types of hyperlipemia have been known, which contain a type that raises the concentration of triglyceride known as a lipid in blood, a type that raises the concentration of cholesterol in blood, and a type that raises both triglyceride and cholesterol in blood. Since remedy of hyperlipemia is important for prevention of myocardial infarction, development for finding new drugs for hyperlipemia provided with excellent activity and safeness is desired.
As the representative drugs for hyperlipemia, pravastatin, simvastatin, clofibrate-type drugs, etc. have been known. However, these drugs are not the one that can reduce the lipid in blood and cholesterol simultaneously and to an equivalent level.
Although a drug which can reduce the amount of triglyceride in blood and cholesterol simultaneously and to an equivalent level and has an effect to prevent peroxidized lipid production has been strongly required in view of remedy and prevention of disease, such as ischemic heart disease induced by arteriosclerosis, myocardial infarction and cerebral infarction, no drug having such effect has been found yet.
Recently, on the other hand, it has been reported that intravital formation of peroxidized lipids and the associating radical reactions thereto give various baneful influence to living organisms via damage to the membranes, cells and the like. Accordingly, various antioxidants and preventing agents for peroxidized lipids production have been tested in order to apply them as a drug for preventing such baneful influence, and research to develop antioxidant drugs have been performed basing upon the chemical structures of the antioxidants and the preventing agents for peroxidized lipids production.
Such antioxidant drugs have been reported, for examples, in J. Amer. Oil Chemists, Soc. 51, 200-203 (1974), JP Laid-opened No. Sho 61-44840, JP Laid-opened No. Hei 1-104033, JP Laid-opened No. 2-121975, EP No. 345593, EP No. 483772, etc., however, the drugs disclosed in these references have problems of insufficient antioxidant effect and unacceptable side effects, and they are not exactly allowable to be used practically.
As the similar compounds to the compounds of the present invention, imidazolylphenyl derivatives, which have an effect to inhibit cholesterol biosynthesis, are disclosed in WO 95/29163.
Further, compounds represented by the following chemical structure are disclosed in DE No. 3,407,505 as a cure for arthritis. 
In addition, although carbonylaminophenylimidazole derivatives are disclosed in JP Laid-opened No. Sho 55-69567 gazette, EP No. 324377 gazette and EP No. 458037 gazette, there is no compound which has an effect to reduce the concentration of lipids in blood, and no cyclic carbonylaminophenylazole compound identical to the compounds of the present invention has been reported.
It is an object of the present invention to provide a drug capable of reducing more amount of triglyceride and cholesterol in blood simultaneously and to an equivalent level than the effect given by conventional drugs and further having an effect to prevent peroxidized lipids production.
After giving investigation to achieve such purpose by the inventors of the present invention, compounds having an effect to remarkably reduce the amounts of triglyceride and cholesterol in blood simultaneously and to an equivalent level were found, and the compounds further having antioxidant effect and an effect to prevent peroxidized lipids production were also found, which thereby constituting the present invention.
The present invention is directed to; (a) phenylazole compounds represented by a general formula (1) and pharmaceutically acceptable salts thereof; 
wherein R1 represents hydrogen or optionally substituted C1-6 alkyl,
A represents imidazolyl optionally substituted with a group represented by following formulas shown below or optionally substituted pyrazolyl, 
wherein R2 and R3 each independently represent optionally substituted C1-6 alkyl, R4 represents optionally substituted C1-6 alkyl, C1-6 alkylcarbonyl or benzoyl, n represents 0 or an integer of 1-3, p represents 0 or an integer of 1-2, and when both n and p are an integer of 2 or more, R2 and R3 may be the same or different,
B represents a group represented by either of the following chemical structures; 
wherein R5 and R6 each independently represent hydrogen, cyano, hydroxy, halogeno, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 acyloxy, C3-6 cycloalkyl, or optionally substituted phenyl, k represents 0 or an integer of 1-15, provided, R5 and R6 may be the same or different when k is an integer of 2 or more;
Y represents a bonding, or O, S, SO2, CO, OCH2, N(R7)CO or N(R7), wherein R7 represents hydrogen or optionally substituted C1-6 alkyl;
Z represents a saturated or unsaturated heterorcyclic group containing 1-4 optionally substituted N, optionally substituted O or optionally substituted S, optionally substituted benzoquinonyl or optionally substituted naphthoquinonyl;
(b) the compounds represented by the general formula (1) described above, wherein Z represents optionally substituted chroman-2-yl, optionally substituted 2,3-dihydrobenzofuran-2-yl, optionally substituted thiochroman-2-yl, optionally substituted 2,3-dihydrobenzothiophen-2-yl, optionally substituted 1,3-benzoxathiol-2-yl, optionally substituted 1,4-benzoquinon-2-yl or optionally substituted 1,4-naphthoquinon-2-yl;
(c) the compounds represented by the general formula (1) described above, wherein Z is a group represented by any of chemical structures (A), (B) and (C) shown below: 
wherein * represents asymmetric carbon atom, X1 represents oxygen or sulfur, and q represents an integer of 1 or 2,
R8, R9, R12, R13 and R14 each independently represent hydrogen or C1-6 alkyl, and R10 and R11 each independently represent hydrogen, C1-6 alkyl or C1-6 alkoxy,
G represents a group represented by either formula of OR15 or NHR16, wherein R15 and R16 each represent hydrogen, C1-6 alkylcarbonyl or optionally substituted benzoyl, R17 and R18 each independently represent hydrogen, methyl or methoxy, or R17 and R18 may form a ring in together represented by a formula, #xe2x80x94CH2CH2CH2xe2x80x94#, xe2x80x9cxe2x80x94CH2CH=CHxe2x80x94#, #xe2x80x94CH=CHCH2xe2x80x94#, #xe2x80x94CH2CH2CH2CH2xe2x80x94#, or #xe2x80x94CH=CHCH=CHxe2x80x94#, wherein # represents that these groups are bonding to a quinone ring at the bonding site of R17 and R18, and R19 represents hydrogen or methyl;
(d) the compounds represented by the general formula (1) described above, wherein Z represents an optionally substituted heterocyclic group, which is furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyranyl, thiopyranyl, piperidinyl, flavonyl, dithiolanyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinoxalinyl, benzthiazolyl, benzoxazolyl, benzoxadinyl, benzimidazolyl, indolyl, indazolyl, 3,4-methylenedioxyphenyl, dihydrofuranopyrimidinyl, dihydrothienopyrimidinyl, dihydropyrrolopyrimidinyl, camphanyl, tetrahydrothianaphthenyl, cyclopenta [2,1-f] indolinyl, imidazopyrimidinyl, pyrrolopyridyl, furanopyridyl or xanthinyl;
(e) the compounds represented by the general formula (1) described above, wherein Z is an optionally substituted heterocyclic group, wherein the substituents are same or different ones selected from a group consisting of hydroxy, nitro, halogeno, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, optionally subituted phenyl, optionally substituted benzyl C1-6 alkylsulfonyl or oxo;
(f) the compounds represented by the general formula (1) described above, wherein A is 1-imidazolyl or 1H-pyrazol-5-yl to be substituted at the 4th position of the benzene ring;
(g) a process to produce the compounds represented by the general formula (1) described above, characterized in that the compounds are produced by dehydrating and condensing an amine compound represented by a general formula (2); 
wherein A and R1 are as defined above, and a carboxylic acid represented by a general formula (3);
HOOC-B-Y-Z xe2x80x83xe2x80x83(3) 
wherein Y and Z are as defined above; (h) a process to produce compounds represented by a general formula (1xe2x80x2); 
wherein A is as defined above, and Bxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are respectively as defined for B, Y and Z except halogenated groups with a halogenating agent, such as hydroxy and amino, by halogenating a carboxylate compound represented by a general formula (3xe2x80x2);
HOOC-Bxe2x80x2-Yxe2x80x2-Zxe2x80x2xe2x80x83xe2x80x83(3xe2x80x2) 
wherein Bxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are as defined above, to prepare an acid chloride represented by a general formula (4);
CIOC-Bxe2x80x2-Yxe2x80x2-Zxe2x80x2xe2x80x83xe2x80x83(4) 
wherein Bxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are as defined above, and subjecting the obtained acid chloride to a reaction with an amine represented by the general formula (2); and (i) drugs for hyperlipemia containing one or more compounds represented by the general formula (1) described above and/or the pharmaceutically acceptable salts thereof as the active pharmaceutical ingredient.